Assessment of renal transplant dysfunction by doppler sonography: A systematic review and meta-analysis

Background: Doppler sonography parameters, particularly the resistive index (RI), have been identified as an essential tool for assessing renal transplant dysfunction (RTD). However, there is some ambiguity in the findings of previous research studies on this matter. Therefore, the objective of our study is to examine the relationship between changes in RI subsequent to RTD. Methods: This was a systematic review and meta-analysis study. We searched three electronic databases PubMed, Web of Science, and Scopus, from the year 2000 to 10 May 2022. The main effect size was considered as the mean RI differences of cases with RTD confirmed by biopsy with control patients with no RTD. We used random effect models to pool the effect size. Results: Thirteen studies were included in our review. The pooled mean (95% CI) for the control group was calculated to be 0.71 (0.67, 0.75) and for patients with renal transplant dysfunction was 0.73 (0.68, 0.78), under a random effect model with high heterogeneity for both analyses (I2=98% and 97%, respectively). The pooled mean was significantly different between the control group and patients with RTD (P= 0.05), based on a t-test of pooled effect sizes. Conclusions: Based on the result of our study, we showed that there is a significant difference between RI in patients with kidney transplant dysfunction and the control group. However, RI cannot substitute kidney biopsy in the management and diagnosis of RTD.

The most frequent reasons for renal transplant dysfunction (RTD) are acute rejection, chronic rejection, and acute tubular necrosis (1).Clinically, it may be difficult to distinguish between these entities.As the number of accomplished renal transplants and the survival rate of these patients rises, providing a noninvasive, accurate approach to identifying the etiology of RTD has become crucial (2,3).Obtaining histopathologic information about a dysfunctional renal transplant is crucial, and one effective method for doing so is through a kidney biopsy.
However, it is important to note that this technique is invasive and may not be suitable for individuals with certain conditions, such as coagulopathy.Additionally, there is a risk of complications from the biopsy, such as the formation of large perinephric hematomas, which can cause or worsen renal failure (4).Sonography has become a standard procedure for assessing renal transplants, as it is a well-established noninvasive imaging examination (5).
On gray-scale imaging of a transplant kidney with malfunction, some morphologic alterations, such as size, parenchymal echogenicity, and corticomedullary differentiation, may be noticed.However, one important issue is that the assessment of renal dysfunction with sonography lack specificity (6).Furthermore, it has been noted that renal sonographic changes appear considerably later than pathological changes, such as an elevated blood creatinine level, once there is already a problem with intrarenal circulation (6).The resistive index (RI) has been used to assess the hemodynamics of both transplanted and natural kidneys (7,8).
The RI has been reported to be a useful Doppler sonography index in the evaluation of kidney transplant dysfunction in certain investigations.(9,10), while other research studies have proven equivocally (11,12).Finally, some publications have shown that comparing follow-up and initial RI values might be beneficial for tracking allograft development, evaluating treatment success, and diagnosing subclinical atherosclerotic damage in transplant recipients' cardiovascular systems.(13).Thus, this study aims at assessing the association of alterations in RI with histopathologic changes in RTDs.

Methods
This study is based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (14).The targeted outcomes were the mean of RI in patients with RTD and the mean of RI in the control group.We searched two international databases (PubMed, Scopus, and Web of Science) for this purpose from the year 200 up to 10 May 2022.
The following keywords were used for searching databases: 1) Kidney transplant, renal transplant, kidney allograft, or renal allograft; 2) Doppler sonography or Doppler ultrasound (Appendix I).No language or type of publication limitation was applied.Eligibility assessment: We included studies that reported data on the mean of RI in both the control group and patients with RTD.Cross-sectional analytical, cohort or case-control studies were included in our study.The RTD had to be diagnosed based on the biopsy or arteriographic method, and biopsy specimens that were not diagnostic for RTD were regarded as controls in the included studies.Studies that contain one or more of the following criteria were excluded: 1) published before 2000, 2) case report or series studies, systematic reviews or meta-analysis studies, grey literature, 3) Studies without a control group, 4) non-English full-texts, and 5) not reported RI as the index of interest.

Literature review and data extraction:
The titles and abstracts of all records which were found in PubMed or Scopus were screened independently by two reviewers.Selected full texts were further screened for the mentioned data and after that, we performed data extraction in an Excel sheet.Any disagreements during data extraction and study selection were discussed with a third reviewer, who was an expert in this field.We extracted the data for the following variables: first author's name, year of publication, definitive diagnosis of patients with renal dysfunction, the gold standard for the definitive diagnosis of RTD, number of the control group, number of patients with kidney transplant dysfunction, mean and standard deviation (SD) of RI in the control group and mean and SD of RI in patients with renal allograft dysfunction.

Study appraisal:
The quality of studies was evaluated based on the New Castle Ottawa Scale (NOS) by two reviewers, and any disagreements during data extraction and study selection were discussed with a fourth reviewer (15).Data synthesis: We used a meta package in the R statistical software (V.4.0.5) for the analysis of our data (16).The pooled mean of RI was calculated for both the control group and patients with renal allograft dysfunction.To examine the heterogeneity of the included studies, we used the I 2 statistic.If heterogeneity was greater than 75%, it would be considered significant heterogeneity, and the randomeffects model was used.(17) The pooled mean for RI was calculated with a 95% confidence interval.To display the result of our meta-analysis, we used the forest plot with the pooled effect and mean for each study.Finally, we used a ttest to compare the two pooled means (SD).We utilized the Egger test to assess the potential publication bias in our study along with the funnel plot visualized by STATA Version 17.

Results
We summarized the study selection process in figure 1.After removing the duplicated studies, 819 records remained.The second phase was title/abstract screening, after which 35 studies remained to be evaluated with their full text.We excluded 22 studies due to the following exclusion criteria 1) 12 studies did not provide sufficient data, 2) 8 studies had no control subjects.Finally, 13 studies were totally eligible for our study.Table 1 summarizes the main findings from each study.We included 13 studies consisting of 1191 control cases and 1115 patients with kidney transplant dysfunction.As some studies had divided subpopulations of RTD, 16 different cohorts of patients were included in our data synthesis.
The mean of RI in the control group ranged from 0.60 to 0.98 and the mean of RI in patients with kidney transplant dysfunction ranged from 0.51 to 0.93.The pooled mean (95% CI) for the control group was calculated to be 0.71 (0,67, 0.75) (figure 2) and for patients with renal transplant dysfunction was 0.73 (0.68, 0.78) (figure 3).
The most studied pathologies were acute rejection followed by renal artery stenosis.The gold standard for diagnosis of renal transplant dysfunction in all studies except one was a biopsy.
The pooled mean effect showed a statistically significant difference between the control group and RTD patients (p< 0.05).As shown in figure 4, there was no potential publication bias in the study due to the symmetry of the plot and Egger test was not significant (P=0.329),showing no publication bias.Quality assessment: Table 2 shows the quality of the studies included in the analysis based on the New Castle Ottawa Scale.The table includes 12 studies and each row represents a study.The columns are divided into three categories: Selection, Ascertainment of Exposure, and Non-Response Rate.The table suggests that the included studies have a low risk of bias and proper method according to the New Castle Ottawa Scale.

Discussion
Our systematic review and meta-analysis study demonstrated a significant difference in the resistive index (RI) between patients with renal transplant dysfunction and the control group.Our findings support the use of Doppler sonography parameters, including RI, as an essential tool for assessing RTD.Greyscale ultrasonography (US), color Doppler ultrasonography (DUS), and contrast-enhanced ultrasonography (CEUS) are examples of US assessment techniques that may be used to assess the morphology and vascular health of an allograft.With the hope of utilizing a noninvasive technology that can detect early renal hemodynamic abnormalities and resultant transplant failure, several experiments have been performed on DUS parameters, with the majority focusing on the RI (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30).Some studies have reported positive results utilizing the RI as a beneficial tool to monitor renal disorders, whereas others have reported negative results when using the RI to assess renal illnesses.Our study showed that there is a significant difference between the RI in patients with renal transplant dysfunction and the control group.According to one study, the location of renal histopathologic alterations mattered more than the severity of changes in causing a higher RI (31).This result was in line with another study, which indicated that disorders of the tubulointerstitial compartment resulted in a higher RI, but diseases affecting only the glomeruli did not (7) .
The RI is measured by subtracting the peak systolic velocity (PSV) and end-diastolic velocity (EDV) divided by the PSV.In theory, a nonproportional change in the PSV, EDV, or both might modify the RI.In clinical practice, various appearances of the DUS waveform and velocity in the interlobar arteries can be caused by changes in renal hemodynamic factors due to alterations in extra or intrarenal conditions.Various extrarenal factors can influence renal blood flow and significantly alter the DUS waveform.These factors include the function of the right side of the heart, cardiac output, blood pressure, and the vascular status of the recipient (32).
In the study conducted by Cano et al., it has been reported that RI is a valuable marker in assessing kidney transplant function.More than 0.7 increase can alert for acute kidney allograft dysfunction.However, it is unable to distinguish between other possible conditions such as acute or chronic rejection, tubular necrosis, renal thrombosis, ureteral obstruction, infection, or medication toxicity (33).Several studies have used RI and PI to effectively evaluate the longterm outcomes instantly following the transplantation (34, Habibi Sh, et al. 35).One study used RI in various transplanted organs, such as kidney grafts, and showed that RI is mostly valuable for detecting systemic vascular pathologies and prediction of death after transplant rather than the diagnosis of specific renal graft dysfunctions (36).Similarly, Heine et al. discovered that a higher RI was linked to subclinical systemic atherosclerosis, high pulse pressure, and diabetes.They could not establish a link between RI and GFR of the kidney (11).Other indices such as PSV and EDV in the interlobar artery should be taken into account when evaluating DUS values and examining the relationships among these measures, clinical presentation, or laboratory test results using DUS to examine kidney transplant hemodynamics.The limitations of our study are as follows: 1) we did not include all doppler ultrasonography parameters; 2) In our study, we did not stratify the data based on histopathological changes.However, the latter is directly caused by a low number of studies in each category.To the best of our knowledge, this is the first meta-analysis comparing the sonographic parameters in patients with kidney allograft dysfunction and control groups.
Our study showed that there is a significant difference between RI in patients with kidney transplant dysfunction and the control group.However, our research suggests that RI cannot substitute kidney biopsy in the management and diagnosis of renal transplants dysfunction.More research on Doppler parameters with the potential to be used in noninvasive kidney transplant hemodynamics should be encouraged.

Figure 1 .
Figure 1.Summary of the study selection process

Figure 2 .Figure 3 .Figure 4 .
Figure 2. Mean of resistive index (RI) in individual studies and pooled mean in the control group (forest plot)